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Inhibition of TNF during maturation of dendritic cells results in the development of semi-mature cells: a potential mechanism for the beneficial effects of TNF blockade in rheumatoid arthritis

A W T van Lieshout¹, P Barrera¹, R L Smeets¹, G J Pesman², P L C M van Riel¹, W B van den Berg¹, T R D J Radstake¹

¹ Department of Rheumatology, University Medical Centre Nijmegen, Nijmegen, Netherlands
² Department of Experimental and Chemical Endocrinology, University Medical Centre Nijmegen

Correspondence to:
Dr T R D J Radstake
University Medical Centre Nijmegen, Geert Grooteplein 8, 6500 HB Nijmegen, Netherlands; t.radstake{at}reuma.umcn.nl

Background: Dendritic cells orchestrate pivotal immunological processes mediated by the production of cytokines and chemokines.

Objective: To assess whether neutralisation of tumour necrosis factor (TNF) during maturation of dendritic cells affects their phenotype and behaviour, which might explain the beneficial effects of TNF neutralisation in rheumatoid arthritis.

Methods: Immature and fully matured dendritic cells were cultured from blood monocytes from patients with rheumatoid arthritis and healthy controls following standardised protocols. TNF was neutralised by addition of the p55 soluble TNF receptor, PEGsTNFRI. The effect of TNF neutralisation on the phenotype (CD14, CD16, CD32, CD64, CD80, CD83, CD86, and MHC) of dendritic cells was investigated by flow cytometry. Expression of chemokines (CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8) and production of IL1ß and IL6 during dendritic cell differentiation and maturation were examined.

Results: Neutralisation of TNF during the differentiation and maturation of dendritic cells did not result in an altered dendritic cell phenotype in the rheumatoid patients or the healthy controls. In contrast, the expression of CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8 by dendritic cells was significantly reduced when TNF activity was inhibited during lipopolysaccharide triggered dendritic cell maturation. The production of IL1ß and IL6 by mature dendritic cells was inhibited by PEGsTNFRI.

Conclusions: Inhibition of TNF activity during dendritic cell maturation leads to the development of semi-mature cells. These data suggest a novel pathway by which the neutralisation of TNF might exert its therapeutic effects.

Abbreviations: APC, antigen presenting cells; CDC, dendritic cells from healthy controls; DAS28, 28 joint disease activity score; FACS, fluorescence activated cell sorting; IL, interleukin; LPS, lipopolysaccharide; MHC, major histocompatibility complex; MIP, macrophage inflammatory protein; RADC, dendritic cells from patients with rheumatoid arthritis; TNF, tumour necrosis factor

Keywords: dendritic cells; tumour necrosis factor ; rheumatoid arthritis; chemokines

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